Case Study: Salbutamol/Salmeterol Flashcards
What is asthma?
Chronic inflammatory disorder of airways in response to external stimuli
What are patients with asthma characterised by?
Inflammation
Bronchospasm
What causes bronchodilation?
Adrenergic system
What causes bronchoconstriction?
Cholinergic system
What is used to treat bronchospasm?
Salbutamol
(Adrenergic agonist)
RELIEVER
What is used to treat inflammation?
Corticosteroid
eg. beclomethasone
Describe brief process of inflammation
Antigen + Ab (IgE)
A-A complex
Bronchoconstriction mediators
= histamine, leukotrienes + prostaglandins
Describe 1st part of asthma drug history
Adrenaline
BUT cardiac effects
Agents similar to adrenaline structure
Isoprenaline = NO cardiac effects BUT short acting
Describe 2nd part of asthma drug history
Adrenoreceptors
Alpha + beta
What were alpha adrenoreceptors defined as?
Sensitive to adrenaline + insensitive to isoprenaline
What were beta adrenoreceptors defined as?
Sensitive to isoprenaline + least sensitive to noradrenaline
Describe the 3rd part of asthma drug history
Beta 1 receptors
Beta 2 receptors
Where are beta 1 receptors found?
Heart
Where are beta 2 receptors found?
Bronchial smooth muscle
Describe the chemistry of noradrenaline + adrenaline
Very similar structure
Both acidic + basic groups
Physiologically behave as a base
= 90% protonated at pH 7.4
Where is noradrenaline synthesised?
In neuron in CNS + autonomic nervous system
Where is noradrenaline + adrenaline derived from?
L-tyrosine by series of enzyme catalysed reactions
What is the aim of metabolism?
To change drugs so they have groups that make them more H2O soluble
What type of receptors are adrenergic receptors?
G protein-coupled receptor
How do adrenergic receptors affect biological activity?
Release secondary messenger molecules inside the cell after the bind an extracellular agonist
How do noradrenaline bind?
Ionic bond
H bonds
Van der Waals
What can noradrenaline interact with?
Alpha/ beta
What can adrenaline interact with?
Alpha/ beta
What does isoprenaline interact with?
Selectively beta
What did the new drug need to be?
STABLE
More selective for beta 2
What did they first decide about the new formula?
Substituent had to be in meta position
What was decided in round 2 of synthesis?
Tert-butyl derivative added
= did increase some activity
What was decided in round 3 of synthesis?
Methyl OH was added in meta position
What did the tert-butyl group prevent?
CYP450 metabolism
What was the only problem with salbutamol now?
(New formulation)
Chiral compound
= enantiomers one more active
How do you separate enantiomers?
One will be insoluble to what the other will be soluble in
Which enantiomer was more active of salbutamol?
R isomer
What do substituents on amine groups determine?
Alpha or beta selectivity
What do substituents on alpha C show?
An increased duration of action
What needs to be substituted for an adrenergic agonist to demonstrate beta 2 selectivity?
Substituted ring:
Phenolic hydroxy in para
Substituent in meta for H bonding
NEEDS to be resistant to COMT metabolism
How long does salbutamol last?
4-6hrs
BUT is a reliver
What is salbutamol inadequate for?
Nocturnal bronchospasm
For a long-acting beta 2 agonist what 2 major sites of interaction must it have?
Active site
Hydrophobic domain for anchoring
What were the 2 main observations from the LABA investigation?
To maintain potency 5-6 Cs
To obtain long duration logP = 3.3 - 4.5
What is the importance of O in LABA investigation?
O placed close to N
O placed close to phenyl ring
Describe the binding of Salmeterol
Reversible
Can be repeated several times
What problem was suggested about salmeterol?
Persists in tissues
BUT interact freely + reversibly
What was the original concept of salmeterol exo-site?
Long chain interacts with non-polar region in cell membrane
“Exo-site” within vicinity of beta receptor
